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Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection.

ABSTRACT: Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. Here we performed a genome-wide CRISPR screen with SARS-CoV-2 and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex and key components of the TGF-β signaling pathway. Small molecule inhibitors of these pathways prevented SARS-CoV-2-induced cell death. We also revealed that the alarmin HMGB1 is critical for SARS-CoV-2 replication. In contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death. Together this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis.

SUBMITTER: Wei J

PROVIDER: S-EPMC7457610 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection

Project description:Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. A genome-wide CRISPR screen with SARS-CoV-2 was performed in Vero-E6 cells (data not provided here), identifying known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex, the alarmin HMGB1, and the transcription factors Smad3 and Smad4. Small molecule inhibitors of these pathways inhibited SARS-CoV-2-infection in both monkey and human cells, demonstrating the conserved role of these genetic hits across species. We also revealed that HMGB1 is a novel regulator of ACE2 expression and critical for SARS-CoV-2 replication. In contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death. Together this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis.

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Project description:Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. Here we performed a genome-wide CRISPR screen with SARS-CoV-2 in Vero-E6 cells, identifying known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex, the alarmin HMGB1, and the transcription factors Smad3 and Smad4. Small molecule inhibitors of these pathways inhibited SARS-CoV-2-infection in both monkey and human cells, demonstrating the conserved role of these genetic hits across species. We also revealed that HMGB1 is a novel regulator of ACE2 expression and critical for SARS-CoV-2 replication. In contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death. Together this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis.

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